Sprayable amorphous antibiotic composition, pressurized container with same, and method of preparing



United SPRAYABLE AMORPHOUS ANTIBIOTIC COMPO- SITION, PRESSURIZEDCONTAINER WITH SAME, AND METHOD OF PREPARING No Drawing. ApplicationApril 20, 1955, Serial No. 502,739

11 Claims. (Cl. 141-692) This invention relates to a sprayableantibiotic composition.

1 Modern antibiotics are finding increased utility in many phases oftreatment of animals and humans. Many antibiotics have been primarilyadministered by injection or orally. It is desirable in many instancesto be able to apply an antibiotic topically to various areas. Thisincludes specialized areas such as the eyes, as well as in general tolarge surfaces such as the surface of the skin. For application to theeye, most antibiotic ophthalmic preparations have been used in the formof ointments based upon petrolatum and are consequently somewhat waterrepellant. This caused some difiiculty in application and also delayedabsorption, as the eye surface is normally coated by aqueous fluids.

When the skin is irritated, as for example by a serious burn orabrasion, the spreading of the antibiotic on the surface presentsproblems. Desirably, the antibiotic should be spread with as littledisturbance to the area as possible and should be capable of beingapplied at any .desired rate.

For the treatment of various dermal, ocular, and mucous membraneinfections or injuries, these requirements have presented seriousproblems.

Spraying the antibiotic on the surface would appear to be desirable.Unfortunately a sprayable composition is not readily devised. If apressure spray container is assembled using chlortetracyclinehydrochloride, for example, the crystalline nature of the materialcauses a mat of needles to form in the spray orifice, and quickly clogsthe discharge valve.

It is therefore an object of this invention to provide a method wherebyantibiotics of the tetracycline group, such as tetracycline orchlortetracycline, may be applied by spraying to a selected surface. Theantibiotic is prescut as a calcium salt, with preferably a localanesthetic and preferably a film forming material to bind the antibioticto the surface to which it is applied. For use in the eye, the filmforming material is omitted.

The antibiotic for use in such a pressurized container must be asubstantially amorphous material. Crystalline materials, when present assuspended solids in spray containers cause difliculty, because theyfrequently crystallize in the fine apertures of the valves. This can bethe case even with finely'subdivided or micronized crystalline a atent O2,782,975 Patented Feb. 26, 1957 with the calcium ions than does thecrystalline form.

substances, as'any trace of soluble material will form A slurry wasprepared containing 42.8 kilograms ofcrystalline chlortetracyclinehydrochloride meeting pharmaceutical standards of purity, in 600 litersof pure water. The chlortetracycline did not dissolve, but formed Over aperiod of approximately 30 minutes to the slurry was added, withcontinous stirring, approximately 4 kilograms of 60 mesh calciumhydroxide, the pH being constantly measured to insure it did not riseabout'9.5. 1.91 kilograms more of calcium hydroxide were added withstirring during the next 30 minutes at such a rate that the pH did notexceed 9.5 during the addition.

Whereas the 5.91 kilograms of calcium hydroxide is approximately thatrequired for theoretical consideration, it was found that to keep the pHat more than 8.5, as the mixture was stirred, an additional 2.5kilograms of calcium hydroxide were required. This was added slowly withstirring until the pH remained at more than 8.5, but less than 9.5.Apparently, part of the calcium hydroxide was required to neutralizecarbon dioxide from the air and to check hydrolysis of the calciumchlortetracycline.

The mixture containing the precipitate of calcium chlortetracycline wasdiluted to 1650 liters with additional water, stirred, and then filteredthrough a filter press. The separated filter-cake was slurried with 300liters of water and run through a comminuting mill. The machine used wasa Fitzpatrick ointment mill operating at 5,000 revolutions per minute.This thoroughly ground the cake and insured that all particles werecompletely disintegrated. The mixed slurry was diluted to 1650 literswith water and again calcium hydroxide was added to readjust the pH to8.5. Approximately 140 grams were required. The slurry was allowed tostand for onehalf hour and again filtered through the filter press. The

precipitate was again slurried with 300 liters of W816i,

passed through the comminuting mill, diluted to 1650 liters, and the pHagain adjusted to 8.5 with calcium hydroxide; again approximately 140grams being required. The composition was stirred for one-half hour andfound to still have a pH of 8.5. The precipitate was separated'by meansof a filter press, and dried. The precipitate was ground until 95 wasless than 5 microns in maximum dimension.

Calcium tetracycline may be prepared in a similar manner.

These calcium salts should be finely divided and dry enough to form afree flowing powder. They may be screened and ground to insure that thedegree of subdivision is suitable for spraying. The particles should be,less than 15 microns in diameter.

The amorphous salt of the antibiotics prepared as above are readilysprayable.

As a propellant it is preferred to use a mixture of the haloalkanes.Among those which may be used are those sold under the trade name Freon.The formulae,

. boiling points and densities of these are as follows:

Trade name Formula Boiling point, Density at C. 30 C.

CChF +23. 77 1. 464 CC12F2 --29. 80 1. 293 GHCIQF +8. 92 1. 354 OHOIF:40. 80 1. .175 CClzFCClFz +4157 1. 553 Freon 114 (CClFm +3, 55 1. 440

3 tion mixed with the calcium salt of the antibiotic under refrigerationor pressure or preferably, the antibiotic may be mixed with the higherboiling components of the haloalkane mixture and filled into acontainer. Then to this may be added under refrigeration or pressure thelower boiling components.

During the spraying of insoluble powdered materials, difficulty has beenencountered in the settling and packing of the suspensions so that whenthe valve is first opened the heavy settled material is immediatelyforced up the dip tube and may clog the valve. This is particularly thecase with fine powders which, although settling slowly, form compactedlayers at the bottom of the container on long standing so that vigorousshaking does not re suspend them into a satisfactory spray dispersion.Specialized containers and valves have been used in an attempt to avoidsuch difiiculties.

If the calcium antibiotic salt is finely subdivided, so that at least95% of it is less than five microns in diameter, the rate of settling incertain haloalkanes is extremely slow. Preferably, a mixture ofhaloalkanes is used such that the specific gravity of the liquid mixturematches insofar as is possible, the density of the powder. If thespecific gravity of the liquid is above about 1.37, it is found that therate of settling of the calcium salt of the antibiotic is so slow thatit does not settle over prolonged periods and may be resuspended byslight agitation of the container. A slightly lower specific gravity ofpropellant may be used if the antibiotic is more finely divided. As aresult, for all intents and purposes, by shaking the container beforeuse there is formed a temporarily nonsettling suspension of the solidantibiotic which will allow the application of the antibiotic toextensive surfaces. Such a suspension will readily spray through a .025inch aperture to form a fine mist. The liquid carrier is almostimmediately volatilized and the suspended medicament thus forms anextremely fine dust of high covering power and potency.

The choice of haloalkanes must be such that not only the specificgravity but also the volatility characteristics are satisfactory. Threetypes of containers are being used at present. (1) A medium-pressurecontainer in which the pressure of the propellant is from about 25 to 45pounds per square inch gauge; (2) a high-pressure container in which thepressure is above 45 pounds per square inch gauge, which frequentlyrequires specially constructed containers; and (3) a low-pressurecontainer of from 12 to 25 pounds per square inch gauge, which may beused with glass containers which have been recently introduced on themarket. The pressures may be measured at 25 C. The choice of the boilingpoint, which controls the pressure, depends in part upon the type ofcontainer and the type of valve which it is desired to use. It ispreferred to use a propellant which does not have a greater pressurethan 200 pounds per square inch at 130 F. (545 C.). It is also preferredto use one which has a vapor pressure of from 38 to 42 pounds per squareinch at a temperature of 25 C. Control of the specific gravity andpressure is easily obtained by using a mixture of propellants usingcertain of the higher boiling point, and certain of the lower boilingpoint haloalkanes so that the characteristics of the spray are asdesired; neither being too coarse nor too fine. The choice ofpropellants is illustrated by certain examples which follow.

Additionally, a local anesthetic forms a valuable componcnt of themixture. (As used in this sense, the term includes analgesics.) Inasmuchas the antibiotic is usually sprayed on an injured area which issensitive, a local anesthetic which desensitizes the area is anadvantage. Such an anesthetic should be one which is preferably solublein the propellant, or of such amorphous insoluble character that it doesnot form crystalline deposits around the valve nozzle. Suitableanesthetics which are soluble in the propellant include such materialsas chlorobutanol, which is 1,1,1 trichloro-Z methyl-2 propanol. Thismaterial is in the anhydrous state and if present in the dispersingfluid to the extent of approximately /z% by Weight, gives a localanesthetic action when sprayed on the surface of the skin or in the eye.As a result, the cooling effect of the propellant and the rapid effectof the local anesthetic give almost immediately a sense of relief to thesubject. Even if sprayed in the eye, the material gives a soothingeffect with almost instantaneous effect of the medicaments. Other localanesthetics which may be used include the derivatives of the ethylesters of paraaminobenzoic acid such as benzocaine, and procaine.

For use on the surface of the skin, as for example, in the treatment ofburns, a protective film is frequently an advantage. A suitablefilm-forming material such as ethyl cellulose which is soluble in thehaloalkanes and which forms a protective covering may be present. From/2 to 2% of ethyl cellulose causes the antibiotic to adhere to thesurface and prolongs its effect. The water insoluble ethyl cellulosealso protects the surface mechanically. From 1 to 2% of a plasticizerfor the ethyl cellulose, such as cetyl alcohol may also be present. Thisalso forms an emollient coating on the treated area. Ethyl celluloseshould not be present in materials which are used directly in the eye.

As illustrative of certain of the compositions within the scope of thisinvention which may be used for the therapeutic application ofantibiotics, certain examples follow:

Example 1 Based on the final contents of the container a mixture wasprepared of 48% by weight of dichlorotetrafiuoroethane and 1% of calciumchlortetracycline prepared as described above, and 0.5% of anhydrouschlorobutanol. The calcium chlortetracycline and the chlorobutanol wereground with the dichlorotetrafiuoroethane and filled into containers sothat the container was half filled. These containers were refrigerated,and under refrigerated c011- ditions there was then added 50% ofdifiuorodichloromethane. While refrigeration was maintained thecontainers were sealed. 0.025 inch aperture valves were used. Thecontainers after being filled, sealed and leak tested were then readyfor use. The specific gravity of the propellant is 1.37. Thepreparations as thus constituted are stable for periods of at leastabout a year at room temperature under normal storage conditions. Justprior to use it is desirable that the container be shaken to resuspendany of the calcium chlortetracycline which may have settled. As thusprepared the formula was found very satisfactory for the treatment ofpink eye in cattle. A small amount of the material was sprayed from 6inches directly into the eyes of the cattle which were to be treated. Ina short time the pink eye was found to respond favorably.

Example 2 A composition similar to Example 1 was prepared using calciumtetracycline as the antibiotic. The mixture was prepared under similarconditions and found to be equally satisfactory for the use in thetreatment of pink eye in cattle. I

It was noted that the specific gravity of the liquid mixturewasapproximately 1.37 and that at a room temperature of about 25 C. thevapor pressure of the mixture in the container was 25 pounds per squareinch.

Example 3 A mixture was prepared containing 47 parts by weight ofdichlorotetrafluoroethane, one part by weight of ethyl cellulose, 2parts by weight of calcium chlortetracycline, and 0.5, part by weight ofchlorobutanol. The composition was trituratedand filled into pressurecontainers.

These were sealed, and under pressure were injected 49 parts by Weightof dichlorodifluoromethane.

The thus-prepared composition was easily sprayed and formed a protectivefilm on the surface of the skin in which the calcium chlortetracyc linewas held in close proximity to the surface of the skin so as to insure aprolonged antibiotic treatment. When applied to the surface of a burn insuch thickness that the ethyl cellulose forms a film thereover a singletreatment is normally sufficient to protect the surface of the burnduring the period of healing. For particularly deep or drastic burns itmay be necessary to apply additional treatments.

The sprayed coating was found efiective in cases of chronic otitis,infectious dermatitis, summer eczema, ear infections, hematoma openings,infected external cavities, skin lesions and other skin and surfaceconditions in which antibiotic sensitive organisms were actually orpotentially present.

Example 4 A mixture is prepared as in the preceding example usingcalcium tetracycline and containing additionally one part by weight ofcetyl alcohol. The thus-prepared mixture when sprayed on the surface ofthe skin formed a flexible film so that it could be used on areas of thebody which were subject to flexure, as for example the elbow or knee.

Example 5 Pressurized containers were prepared by triturating one partof calcium chlortetracycline, /2 part of chlorobutanol and 75 parts oftrichlorofluoromethane. The mixture was ground together until thoroughlymixed and homogeneous and filled into pressurized containers. Theretoare added 25 parts of dichlorodifluorornethane under refrigeratedconditions and the containers sealed. The containers were permitted toWarm to room tem perature and found to be satisfactory for spraying intothe eyes of humans or animals.

I claim:

1. A method of preparing a pressurized container comprising mixingtogether a substantially amorphous antibiotic selected from the groupconsisting of calcium chlortetracyc'line and calcium tetracycline havingparticle sizes less than microns and a haloalkane which may be handleddirectly under room conditions, filling the composition into a suitablemetal container, and adding thereto a more volatile haloalkane.

2. A method of preparing a pressurized container comprising mixingtogether a substantially amorphous antibiotic selected from the groupconsisting of calcium chlortetracycline and calcium tetracycline havingparticle sizes less than 15 microns and a haloalkane which may behandled directly under room conditions, filling the composition into asuitable metal container, and adding thereto under refrigeratedconditions a more volatile haloalkane, then sealing the container.

3. A method of preparing a pressurized container comprising mixingtogether a substantially amorphous antibiotic selected from the groupconsisting of calcium chlortetracycline and calcium tetracycline havingparticle sizes less than 15 microns and a haloalkane which may behandled directly under room conditions, filling the composition into asuitable metal container, sealing the container, then adding underpressure, a more volatile haloalkane.

4. A pressurized container containing a mixture of haloalkanes whosespecific gravity is greater than approximately 1.37 and whose vaporpressure at 25 C. is between about 12 and about pounds per square inchgauge and a substantially amorphous tetracycline group antibioticselected from the group consisting of calcium chlortetracycline andcalcium tetracycline having particle sizes less than 15 microns.

5. The composition of claim 11 which comprises a local anesthetic.

6. The composition of claim 5 comprising chlorobutanol as a localanesthetic.

7. The composition of claim 5 comprising from approximately 1 to 2% ofethyl cellulose.

8. The composition of claim 7 comprising from approximately 1 to 2% ofcetyl alcohol.

9. A pressurized container containing 1 to 2% of calciumchlortetracycline the average particle size being less than 5 microns indiameter, approximately /z% of chlorobutanol and a mixture ofapproximately equal parts of dichlorotetrafluoroethane anddichlorodifluoromethane.

10. A pressurized container containing 1 to 2% of calciumchlortetracycline the average particle size being less than 5 microns indiameter, approximately of chloretone, approximately 1% ethyl celluloseand a mixture of approximately equal parts of dichlorotetrafluoroethaneand dichlorodifluoromethane.

11. A composition of matter comprising finely divided particles having adiameter of less than about 15 microns of a substantially amorphousantibiotic of the group consisting of calcium chlortetracycline andcalcium tetracycline suspended in a liquid haloalkane whose specificgravity is greater than 1.73 and whose vapor pressure at 25 C. isbetween 12 and 100 lbs/square inch.

References Cited in the file of this patent UNITED STATES PATENTS2,609,329 Niedercom Sept. 2, 1952 2,621,014 Efford Dec. 9, 19522,699,054 Conover Jan. 11, 1955 2,727,665 Charney Dec. 20, 1955 FOREIGNPATENTS 1,032,567 France Apr. 1, 1953 1,085,274 France July 21, 19547/1954 Trinidad Mar. 26, 1954 OTHER REFERENCES Goodhue: Low and ModeratePressure Liquefied-Gas Aserosols. Ind. & Eng. Chem, July 1949, pages1523- 1 27.

Du Pont: Technical BulL, June 1951, vol. 7, No. 2, pages 81-86, FineChemicals Products for the Aerosol Industry.

11. A COMPOSITION OF MATTER COMPRISING FINELY DIVIDED PARTICLES HAVING ADIAMETER OF LESS THAN ABOUT 15 MICRONS OF A SUBSTANTIALLY AMORPHOUSANTIBIOTIC OF THE GROUP CONSISTING OF CALCIUM CHLORTETRACYCLINE ANDCALCIUM TETRACYCLINE SUSPENDED IN A LIQUID HALOAKANE WHOSE SPECIFICGRAVITY IS GREATER THAN 1.73 AND WHOSE VAPOR PRESSURE AT 25* C. ISBETWEEN 12 AND 100 LBS/SQUARE INCH.